Being necessary for orderly growth and differentiation of tissues, vitamin A is one of the most important micronutrients affecting the health of children. In the developing world, vitamin A supplementation programmes significantly reduce infant mortality as well as the incidence of xerophthalmia, respiratory infection, and morbidity from gastrointestinal disease. Supplementing newborn infants with vitamin A within 48 hours of birth reduces infant mortality by almost a quarter, with the greatest benefit to those of low birth weight. In the developed world, most infants and children are vitamin A sufficient. Term infants are well supplied with vitamin A in utero, and both human milk and infant formulae contain adequate amounts of vitamin A for normal growth and health. Unfortunately, vitamin A sufficiency cannot be assumed for preterm infants. Born with inadequate body stores of vitamin A and often unable to tolerate routine oral supplementation, they are prone to diseases of the eye and respiratory and gastrointestinal tract (Mactier and Weaver, Arch Dis Child Fetal Neonatal Ed 2005; 90: F103-F108).
Due to their immature gastrointestinal tract, many low birth weight and almost all extremely low birth weight infants cannot absorb and digest enteral nutrition in the first days after birth.
Thus, parenteral administration is the only suitable route for supplementing these infants with vitamin A.
Presently, the recommended doses for parenterally administered vitamin A vary between 700 and 1700 International Units per kg per day.
In order to warrant flexible, individual and independent vitamin A dosing, vitamin A should advantageously be available as a mono vitamin product rather than being fixed part of a pre-mixed multivitamin preparation.
To our knowledge, there is only one such vitamin A product commercially available for parenteral supplementation of vitamin A: Aquasol A™ (Hospira). The product is an aqueous solution of vitamin A and comprises 15 mg retinol (50000 IU, as retinol palmitate) per ml of the composition. Further ingredients are chlorobutanol (as a preservative) and polysorbate (as a solubilizer; retinol palmitate is practically insoluble in water). Aquasol A™ is approved for intramuscular application.
Intramuscular injection, however, is extremely painful, especially to newborn infants, and may cause infections, tissue irritations, muscle damage, haematomas and nerve lesions. More severely, polysorbates have been associated with the E-Ferol syndrome (thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis) in low birthweight infants.
U.S. Pat. No. 5,925,684 relates to emulsions for parenteral administration comprising at least one carotenoid in a concentration of 0.1 to 10 wt. %. These emulsions are stabilized by means of Poloxamer 188.
Carotenoids have the tendency to stick to plastic surfaces and are thus not ideal vitamin A derivatives for the preparation of storage stable vitamin A compositions.
Poloxamers are synthetic polyoxyethylene/polyoxypropylene block copolymers that may cause allergy and/or intolerance.
Thus there is a need for compositions overcoming the drawbacks described above, i.e. there is a need for safe, compatible and stable compositions suitable for the parenteral supplementation of vitamin A, specifically for compositions that may readily be administered intravenously and be mixed with customary parenteral nutrition products.